Active agents, specifically therapeutic agents, conjugated to biocompatible linkers and their use in forming the backbone of polymeric drug delivery systems are known. For example, U.S. Pat. No. 6,486,214 to Uhrich discloses the tethering of two drug molecules via an aliphatic linker and the subsequent polymerization of these compositions through the formation of anhydride linkages between the drug moieties. In Uhrich, the moiety that connects the aliphatic linker to the drug molecule is an amide, thioamide, ester or thioester group. Uhrich further discloses that these polyanhydrides may be used as vehicles for the clinical delivery of the linked drug upon degradation of the polymer to its drug and biocompatible linker components.
Other aliphatic linkers have been disclosed in Australian Patent No. 750,424 to Uhrich, U.S. App. Pub. No. 20050131199 A1 and U.S. App. Pub. No. 20050048121 A1. In addition to aliphatic linkers, AU 750,424 discloses in general terms linkers with a backbone of an alkylene group having one to twenty carbon atoms and linkers with a backbone of two to twenty carbon atoms having a structure selected from (—CH2—CH2—O—)m, (—CH2—CH2—CH2—O—)m, and (—CH2—CHCH3—O—)m. In addition to aliphatic linkers, U.S. App. Pub. Nos. 20050131199 A1 and 20050048121 A1 disclose in general terms linkers where one or more of the carbon atoms of the aliphatic chain linker are substituted with one or more oxygen or nitrogen atoms. The therapeutic agent-linker conjugates of these applications are used as monomers to form oligomeric and polymeric drug delivery compositions.
U.S. Pat. No. 5,840,900 to Greenwald et al. discloses the use of a substantially non-antigenic polymer as a linker to form a drug-linker prodrug. The backbones of these linkers are polyalkylene oxide derivatives, preferably polyethylene glycol derivatives having a molecular weight above 20,000 Daltons. Further polymerization of these conjugates is not taught.
U.S. App. Pub. No. 20050048121 A1 discloses copolymers of aliphatically-linked diflunisal monomers with either lactate or glycolate diol co-linkers, which contain the α-hydroxy carboxylic acid ester functionality, for use as vehicles to deliver diflunisal upon degradation. German patents DE 223305 and DE 227999 disclose diglycolic acid-linked salicylic acid. DE 227999 discloses that it can be used therapeutically to overcome the stomach-irritating effects of salicylic acid alone while maintaining potency. DE 223305 teaches that the compounds are useful as medicaments. In addition, Greenwald discloses in general terms the conjugation of its polymer linkers to a drug via α-hydroxy carboxylic acid ester groups, among others. However, Greenwald also teaches that the degradation rate of its prodrugs depends not only the type of linking moiety used, but also on whether the polymer linker possesses sufficiently high molecular weight.